Diltiazem is a benzothiazine derivative possessing calcium antagonist activity. Diltiazem blocks the influx of calcium ions in smooth and cardiac muscle and thus exerts potent cardio-vascular effects. Diltiazem has been shown to be useful in alleviating symptoms of chronic heart disease, particularly angina pectoris and myocardial ischemia and hypertension, while displaying a low incidence of side effects. The first dosage forms of diltiazem sold in the United States were tablets containing 30 mg or 60 mg of diltiazem hydrochloride sold under the tradename Cardizem by Marion Laboratories Inc. Single oral doses of 30 mg and to 120 mg of Cardizem tablets result in peak plasma levels about 2 to 3 hours after ingestion, and the elimination half-life is about 3 to 5 hours. Because of the relatively rapid absorption of diltiazem hydrochloride from such tablets and rapid elimination, the usual dosage regimen for immediate release tablets is for a dose to be taken three or four times daily. The need for such frequent administration may reduce patient compliance. Thus adverse therapeutic effects can arise. It thus became apparent that it would be preferable to administer diltiazem hydrochloride in a dosage form that releases the diltiazem hydrochloride much more slowly than Cardizem tablets, so as to enable the frequency of ingestion by the patient to be reduced to once daily.
A formulation of diltiazem hydrochloride that controls the rate of release to enable once daily administration is sold in the United States under the tradename Dilacor XR by Rhone-Poulenc Rorer Pharmaceuticals Inc.
Dilacor XR is produced as two-piece hard gelatin capsules, with each capsule containing a plurality of tablets. The 180 mg strength of Dilacor XR contains three tablets and the 240 mg strength contains four tablets. The same tablets are used in both capsules, and each tablet contains 60 mg of diltiazem hydrochloride.
The tablets used in Dilacor XR are made in accordance with the invention of U.S. Pat. No. 4,839,177.
Each tablet is comprised of a cylindrical core containing diltiazem hydrochloride mixed with inactive ingredients which include a polymer that swells and forms a gel upon contact with aqueous fluids. Because the gel has high viscosity it swells and dissolves only very slowly in the gastrointestinal fluids to thereby retard the rate of release of the diltiazem hydrochloride. To further retard the release, insoluble polymeric platforms are affixed to the top and bottom of the cylindrical core, thus leaving only the periphery exposed to the gastrointestinal fluid. The formulation of Dilacor XR capsules successfully accomplishes gradual release to enable once daily dosing, but the Dilacor XR formulation requires complex and expensive procedures to produce. In particular, production of the tablets contained in Dilacor XR capsules requires production of cores containing the diltiazem hydrochloride and the affixing thereto of the insoluble platforms.
Another formulation of diltiazem hydrochloride suitable for once daily administration is now sold in the United States under the trademark Cardizem CD, by Marion Laboratories Inc. Cardizem CD is sold as capsules containing a multitude of beads. The composition of the beads contained in Cardizem CD capsules is described in U.S. Pat. No. 5,286,497. The beads are made using core seeds to which is applied a first coating containing the diltiazem hydrochloride. Over the first coating, further coatings of polymers are applied which serve to slow down and control the rate at which the diltiazem hydrochloride is released from the beads in gastrointestinal fluids.
As explained in U.S. Pat. No. 5,286,497, there is a particular dissolution profile found to be optimum for once daily administration. This desired dissolution profile, when measured in a type 2 dissolution apparatus according to U.S. Pharmacopoeia XXII, in 0.1 NHCL at 100 rpm is as follows:
a) from 20-45% released after 6 hours PA1 b) from 25-50% released after 12 hours PA1 c) from 35-70% released after 18 hours PA1 d) not less than 70% released after 24 hours PA1 e) not less than 85% released after 30 hours
The invention of U.S. Pat. No. 5,286,497 achieves this dissolution profile by using a mixture of beads with two differing amounts of coating.
The beads with the lesser amount of coatings are referred to as "rapid release diltiazem beads" and the beads with the greater amount of coating are referred to as "delayed release diltiazem beads".
It is disclosed that by making each of these types of beads so as to comply with particular dissolution requirements, the mixture of the two types of beads produces the desired dissolution profile for the final composition.
A difficulty with the invention of U.S. Pat. No. 5,286,497 is that it is difficult to reliably make the two types of beads so as to get the required dissolution profile for the final mixture.
In particular, the desired dissolution profile requires that the amount released must exceed 20% after 6 hours, but must not exceed 50% after 12 hours.
This requires that the "rapid release diltiazem beads" give a sharp step-like release of the diltiazem. Otherwise, if the amount released increases only gradually with time, beads formulated to assure that at least 20% of the diltiazem is released from the final mix after 5 hours will also cause more than 50% to be released after 10 hours, thus causing the final composition to fail to meet requirements.
In view of the aforesaid problems with prior art formulations, it is an object of the invention to produce a composition of diltiazem hydrochloride suitable for once daily administration, in the form of a blend of beads that overcomes the difficulty in achieving the required dissolution profile that results from using a mixture of only two types of beads.